N-Phenethylaminopropiophenones as lipogenesis inhibitors

ABSTRACT

Certain N-phenethylaminopropiophenones inhibit lipogenesis in mammals.

This is a division, of application Ser. No. 115,467, filed Jan. 25,1980.

DESCRIPTION OF THE INVENTION

It has been found that lipogenesis in mammals is inhibited by certainN-phenethylaminopropiophenones, described by the formula: ##STR1##wherein R is a hydrogen or hydroxyl;

R¹ is hydrogen or methyl;

R² is hydrogen or methyl;

n is zero, one or two;

X is hydroxyl, with the proviso that when n is one, the hydroxyl moietyis bonded to the carbon atom at the 4-position in the phenyl ring, andwhen n is two, the hydroxyl moieties are bonded to the carbon atoms inthe 3- and 4-positions of the phenyl ring;

m is zero or one;

Y is one of

nitro;

cyano;

hydroxyl;

alkyl;

alkoxy;

alkylthio;

alkanoyloxy;

alkenoyloxy;

alkanoylamino;

alkenoylamino;

alkoxycarbonylamino;

alkenyloxycarbonylamino;

3-(dialkylamino)alkyleneoxy;

2-(dialkenylamino)alkyleneoxy,

and their pharmacologically acceptable acid addition salts.

In these compounds, each alkyl moiety contains from one to six carbonatoms, each alkenyl moiety contains from three to six carbon atoms, andeach type of moiety is straight-chain or branched-chain inconfiguration, while each alkylene moiety is ethylene, or ethylenesubstituted by methyl on the carbon atom bonded to the nitrogen atom ofthe aminoalkyleneoxy moiety.

Suitable salts are those of such acids as acetic, succinic, maleic,fumaric, propionic, citric, lactic, pamoic, hydrochloric, hydrobromic,sulfuric and phosphoric acids.

Compounds of Formula I that contain a chiral center are usually obtainedas the racemic mixtures. Such mixtures can be resolved by knowntechniques. The isomers may have different activities as lipogenesisinhibitors. This invention contemplates all of the active isomers, aswell as mixtures thereof.

The compounds of Formula I are known, being disclosed in U.S. Pat. Nos.3,225,095, 3,644,525, 3,829,469; British Pat. No. 1,332,930, and GermanPat. No. 1,815,618.

Compounds of Formula I have been found to inhibit lipogenesis in tissuesof mammals. The manner in which they cause this effect is not known withcertainty; it is believed that they interfere with the synthesis offatty acids in the tissues. Their effectiveness for this purpose hasbeen ascertained by immersing samples of swine adipose tissue in aliquid medium containing radioactive glucose and the test chemical, fora period of time, then isolating the lipid from the treated tissue anddetermining the incorporation of the radioactive carbon into lipid bymeans of scintillation counting techniques. These tests were conductedin swine adipose tissue because in swine, the primary site oflipogenesis--i.e., fatty acid synthesis--appears to be adipose tissue.

Described in more detail, the tests were conducted according to thefollowing general procedure:

150 milligrams of slices of swine adipose tissue were incubated at 37°C. for 2 hours with shaking in 3 milliliters of Krebs-Ringer bicarbonatesolution containing one-half the normal calcium ion concentration, 60micromoles of glucose, 0.5 micro-Curie of glucose-U¹⁴ C, and 300microunits of insulin, and 5% dimethyl sulfoxide (DMSO). The testcompounds were added as suspensions or solutions in DMSO and werepresent at a concentration of 100 micrograms per milliliter of theincubation mixture.

The incubation was terminated by addition of 0.25 milliliter of 1 Nsulfuric acid. The resulting mixture was extracted with a total of 25milliliters of chloroform:methanol (2:1 v/v). The extracts were washedaccording to Folch et al. (J. Biol. Chem., 226, 497-509, (1957)),air-dried, and counted in a liquid scintillation counter with 15milliliters of counting fluid (two parts toluene containing 0.4% w/v NewEngland Nuclear Omnifluor: 1 part Triton X-100). The tests wereconducted in triplicate and were accompanied by control tests in whichall ingredients, proportions and conditions were the same except that notest compound was included. From the data obtained were calculated thepercent inhibition of lipid synthesis by the test compound in each case.

The following individual species of Formula I were tested:

    ______________________________________                                        Com-                                                                          pound                                                                         No.   Where Known  Name                                                       ______________________________________                                        1     G.B. 1,332,930                                                                             N-(3-(3-(2-hydroxy-2-(4-hydroxy-                                              phenyl)-1-methylethylamino)-1-oxo-                                            propyl)phenyl)-3-methyl-2-buten-                                              amide, hydrochloride.                                      2     G.B. 1,332,930                                                                             (4-(3-(2-hydroxy-2-(4-hydroxy-                                                phenyl)-1-methylethylamino)-1-                                                oxopropyl)phenyl)carbamic acid,                                               ethyl ester, hydrochloride.                                3     G.B. 1,332,930                                                                             3-methyl-3-(3-(2-hydroxy-2-(4-                                                hydroxyphenyl)-1-methylethyl-                                                 amino)-1-oxopropyl)-2-butenoic                                                acid, phenyl ester, hydrochloride.                         4     Germany      3-(2-hydroxy-2-(4-hydroxyphenyl)-                                1,815,618    1-methylethylamino)-1-(3-propoxy-                                             phenyl)-1-propanone, hydrochloride.                        5     Germany      3-(3-(2-hydroxy-2-(4-hydroxyphenyl)-                             1,815,618    1-methylethylamino)-1-oxopropyl)-                                             benzonitrile, hydrochloride.                               6     Germany      1-(3-ethoxyphenyl)-3-(2-hydroxy-2-                               1,815,618    (4-hydroxyphenyl)-1-methylethyl-                                              amino)-1-propanone, hydrochloride.                         7     Germany      3-(2-hydroxy-2-(4-hydroxyphenyl)-                                1,815,618    1-methylethylamino)-1-(3-(1-methyl-                                           ethoxy)phenyl-1-propanone, hydro-                                             chloride.                                                  8     U.S. Pat. No.                                                                              3-(2-hydroxy-2-(4-hydroxyphenyl)-                                3,644,525    propylamino)-1-(3-nitrophenyl)-1-                                             propanone, hydrochloride.                                  9     U.S. Pat. No.                                                                              3-(2-(3,4-dihydroxyphenyl)-2-hydroxy-                            3,644,525    ethylamino)-1-(4-methoxyphenyl)-1-                                            propanone, hydrochloride.                                  10    U.S. Pat. No.                                                                              3-(2-(3,4-dihydroxyphenyl)-2-hydroxy-                            3,644,525    ethylamino)-1-(2-hydroxyphenyl)-1-                                            propanone, hydrochloride.                                  11    U.S. Pat. No.                                                                              3-((2-hydroxy-2-(4-hydroxyphenyl)-                               3,644,525    ethyl)methylamino)-1-phenyl-1-                                                propanone, hydrochloride.                                  12    U.S. Pat. No.                                                                              3-(2-(3,4-dihydroxyphenyl)-2-hydroxy-                            3,644,525    ethylamino)-1-phenyl-1-propanone,                                             hydrochloride.                                             13    U.S. Pat. No.                                                                              1-(4-(2-(di-2-propenylamino)ethoxy)-                             3,829,469    phenyl)-3-(2-hydroxy-2-(4-hydroxy-                                            phenyl)-1-methylethylamino)-1-                                                propanone, dihydrochloride.                                14    U.S. Pat. No.                                                                              1-(4-(3-(dimethylamino)-2-methyl-                                3,829,469    propoxy)phenyl)-3-(2-hydroxy-2-(4-                                            hydroxyphenyl)-1-methylethylamino)-                                           1-propanone, dihydrochloride.                              15    U.S. Pat. No.                                                                              (R-(R*,S*))-3-((2-hydroxy-1-methyl-                              3,225,095    2-phenylethyl)amino)-1-(3-methoxy-                                            phenyl)-1-propanone, hydrochloride.                        ______________________________________                                    

The data obtained from the tests are set out in Table 1, as the percentinhibition of lipogenesis compared to the results obtained in thecontrol tests wherein only the test compound was omitted.

                  TABLE 1                                                         ______________________________________                                        Compound No.       Percent Inhibition                                         ______________________________________                                        1                  99                                                         2                  97                                                         3                  92                                                         4                  92                                                         5                  100                                                        6                  89                                                         7                  94                                                         8                  100                                                        9                  88                                                         10                 97                                                         11                 100                                                        12                 97                                                         13                 82                                                         14                 96                                                         15                 100                                                        ______________________________________                                    

The ketones of Formula I can be used to control lipogenesis inwarm-blooded animals such as, for example, pets, animals in a zoo,livestock, fur-bearing animals and domestic animals, including but notlimited to dogs, cats, mink, sheep, goats, swine, cattle, horses, mulesand donkeys. The effect is obtained by administering an effective amountof one or a mixture of two or more of the ketones orally or parenterallyto the animal. They may be administered as such, or as an activeingredient of a conventional pharmaceutical formulation. They may beadministered orally by any convenient means. Thus, they may be orallyadministered as a drench, by intubation, in the animal's food and water,in a food supplement or in a formulation expressly designed foradministration of the drug. Suitable formulations include solutions,suspensions, dispersions, emulsions, tablets, boluses, powders,granules, capsules, syrups and elixirs. For parental administration,they may be in the form of a solution, suspension, dispersion oremulsion. They can be administered in the form of an implant or othercontrolled sustained release formulation. Inert carriers, such as one ormore of water, edible oil, gelatin, lactose, starch, magnesium sterate,talc or vegetable gum can be used. The dosage of the ketone needed toinhibit lipogenesis will depend upon the particular ketone used, and theparticular animal being treated. However, in general, satisfactoryresults are obtained when the ketone are administered in a dosage offrom about 1 to about 400 milligrams per kilogram of the animal's bodywieght. The ketone can be administered in a single dose or in a seriesof doses in the same day, or over a period of days. For any particularanimal, a specific dosage regimen should adjusted according to theindividual need, the particular ketone(s) used as the inhibitor, and theprofessional judgment of the person administering or supervising theadministration of the inhibitor. It is to be understood that the dosagesset forth herein are exemplary only, and that they do not, to anyextent, limit the scope or practice of the invention.

What is claimed:
 1. A method of inhibiting lipogenesis in a mammal,which comprises administering, to a mammal in need of such treatment,orally or parenterally a lipogenesis inhibiting amount of a compound ofthe formula: ##STR2## wherein R is hydrogen or hydroxyl;R¹ is hydrogenor methyl; R² is hydrogen or methyl; n is zero, one or two; X ishydroxyl, with the proviso that when n is one, the hydroxyl moiety isbonded to the carbon atom at the 4-position in the phenyl ring, and whenn is two, the hydroxyl moieties are bonded to the carbon atoms in the 3-and 4-positions of the phenyl ring; m is one; Y is one ofnitro;hydroxyl; alkyl; alkoxy; alkylthio; alkanoylamino; alkenoylamino;3-(dialkylamino)alkyleneoxy; 2-(dialkenylamino)alkyleneoxy, and theirpharmacologically acceptable acid addition salts.